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(11) | EP 0 668 857 B1 |
| (12) | EUROPEAN PATENT SPECIFICATION |
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| (54) |
PROCESS FOR THE PREPARATION OF TRIAZOLONE COMPOUNDS VERFAHREN ZUR HERSTELLUNG VON TRIAZOLONDERIVATEN PROCEDE D'ELABORATION DE COMPOSES DE TRIAZOLONE |
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| Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
[0002] More particularly, it relates to a process for the preparation of a 1,2,4-triazol-3-one compound substituted in the positions 4 and 5 by an alkyl or aryl group and optionally substituted in the position 2 by an alkyl group.
[0003] 1,2,4-triazol-3-ones compounds bi-substituted in positions 4 and 5 or tri-substituted in positions 2, 4 and 5 are useful in themselves or as intermediates. Examples of the said compounds useful for human or animal therapy are described by US-A-3,857,845 and US-A-4,338,317.
[0006] US-A-4,338,317 teaches to preparare the compounds of the formula:
where R is ethyl, R' is hydrogen or phenoxyethyl, and R" is 4-(halophenyl)-1-piperazinyl-propyl, by reacting an N-ethoxycarboxythiopropionamide of the formula:
where R and R' have the meanings set forth above, with a hydrazine compound of the formula:
H2N-NH-R" (III)
where R" has the meanings set forth above.
[0007] However, this process presents a drawback in that during the reaction of compound (II) with compound (III) a highly toxic gas, i.e. hydrogen sulfide, is produced.
[0008] In addition, although the above-mentioned document states that the 1,2,4-triazol-3-one compounds tri-substituted in positions 2, 4 and 5 can be prepared directly from the compounds (II) wherein R' is not hydrogen, it does not disclose any examples of the preparation thereof.
[0009] In a subsequent document, G.D. Madding et al. (J. Het. Chem. 22, 1121-26, 1985) state that the said procedure is suitable only for preparing the intermediate compound bi-substituted in positions 2 and 5, from which the desired tri-substituted compound is then prepared by alkylation. Moreover, even though these Authors don't refer specifically to the production of hydrogen sulfide, they recognize the existence of "factors" which prompt to search for other synthesis pathways.
[0010] Then, G.D. Madding et al. (loc. cit.) describe two other routes for preparing bi-substituted intermediates from which the desired tri-substituted compound is prepared by alkylation.
[0011] The first route involves the cyclization in an alkaline medium of a semicarbazide of the formula:
R'-NH-CO-NH-NH-CO-R (IV)
where R' is phenoxyethyl and R is ethyl.
[0012] In turn the semicarbazide compound (IV) is obtained from an isocyanate compound of the formula:
R'-N=CO (V)
where R' has the meanings set forth in connection with formula (IV), and a hydrazide compound of the formula:
H2N-NH-CO-R (VI)
where R has the meanings set forth in connection with formula (IV).
[0013] Hence, this synthesis has the drawback of using isocyanate compounds which are dangerous and toxic, particularly when they have a low molecular weight and are volatile.
[0014] On the other hand, through this pathway H. Gehlen et al. (Ann. 675, 180-188, 1964) had already prepared several compounds of formula I, in which the position 4 is substituted by an alkyl or aryl group and position 5 is substituted by an alkyl group.
[0015] However, to prepare the compounds which are tri-substituted in positions 2, 4 and 5, H. Gehlen et al. had to employ another method and the only substituent in position 2 was the phenyl group. Therefore, the tri-substituted compounds prepared by these Authors differ from the compounds which are intended to be prepared according to this invention.
[0016] The second route described by G.D. Madding et al. involves the cyclization in a basic medium of an N-carbomethoxyamidrazone compound of the formula:
where R' is phenoxyethyl.
[0017] In turn, compound (VII) is prepared by reacting a compound of the formula:
where R' is phenoxyethyl,
with methyl carbazate and the compound of formula (VIII) is obtained by treating an amide of the formula:
R'-NH-CO-C2H5 (IX)
where R' is phenoxyethyl,
with phosgene.
[0019] Notwithstanding this drawback, the Authors regard this method as the most suitable for large-scale production.
[0020] The fact that such a complex process, which does not directly produce the desired tri-substituted compound and involves the use of a dangerous and toxic gas such as phosgene, is considered to be the best one among the methods investigated by the Authors points cut the difficulties that a person skilled in the art must face in the preparation of a compound of formula (I) where R and R' are alkyl or aryl and R" is hydrogen or alkyl.
[0021] Therefore, it is still needed a process suitable for directly yielding tri-substituted compounds without involving the use and/or the concurrent production of toxic and dangerous substances.
[0022] Surprisingly, it has now be found that this aim may be achieved by condensing a suitable ester of an N-substituted carbamic acid with an optionally N-substituted hydrazide of a carboxylic acid, in the presence of a strong base.
[0023] Therefore, it is an object of this invention to provide a process for preparing a 1,2,4-triazol-3-one compound according to claim 1.
[0024] Examples of suitable strong bases are the hydroxides and alcoholates of alkali metals and mixtures thereof, sodium hydride and sodium amide. Preferably, the alkali metal is sodium or potassium.
[0025] The reaction is preferably performed under conditions which allow to remove the water and alcohol as they form during the reaction. Examples of suitable conditions are, for example, the use of dehydrating agents and the heating to a temperature at which the volatile substances evaporate.
[0026] The reaction temperature is selected so as to prevent significant degradation of the reactants but at the same time complete the reaction quickly to reduce production times to an economic minimum. One of the most widely known and effective techniques to maintain both factors under control lies in the addition of a suitable diluent.
[0027] Therefore, the process of this invention is preferably carried out in the presence of a diluent and at a temperature of from -40°C to 200°C.
[0028] When the strong base is sodium hydride, an alkali metal hydroxide, an alkali metal alcoholate or a mixture thereof, the diluent is preferably selected from those which are immiscible or very poorly miscible with water at their boiling temperature so that the water and alcohol which form during the reaction are removed as an azeotrope.
[0029] Examples of particularly suitable diluents for this step are aliphatic cyclic hydrocarbons such as methylcyclohexane and aromatic hydrocarbons such as toluene and xylene.
[0030] However, when the strong base is sodium amide, the reaction is preferably performed in the presence of liquid ammonia.
[0031] The process of this invention is preferably carried out by reacting, under the above-mentioned conditions, 1 mole of a carbamic acid ester of the formula:
R'-NH-COOY (X)
where
Y is C1-C5 alkyl,
with from 0.5 to 3 moles of a carboxylic acid hydrazide of the formula:
R"-NH-NH-CO-R (XI)
where R, R' and R" are as indicated below,
to yield a 1,2,4-triazol-3-one compound (I) where R, R', R" have the meanings set forth above in connection with the compounds of formula (X) and (XI). As already mentioned, the reaction produces water and an alcohol of the formula YOH, where Y has the meaning set forth above connection with the compound of formula (X).
[0032] R, R' and R" according to this invention are as follows:
- R is phenyl and C1-C10 alkyl optionally substituted by a phenyl group,
- R' is phenyl, halophenyl and C1-C10 alkyl optionally substituted by phenyl or phenoxy,
- R" is hydrogen and C1-C10 alkyl optionally substituted by an heterocyclic group.
[0036] The following examples are intended to illustrate the present invention without, however, limiting it in any way.
Example 1
2[3[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2phenoxyethyl)-1,2,4-triazol-3-one (nefazodone) hydrochloride. (Formula I: R = ethyl; R' = phenoxyethyl; R" = 3[4(3-chlorophenyl)-1-piperazinyl]propyl)
[0037] N-3[4-(3-chlorophenyl)-1-piperazinyl]-propyl-N'-propionylhydrazine (32.5 g; 0.1 moles) (prepared by reacting ethyl propionate with the N-3[4-(3-chlorophenyl)-1-piperazinyl]propyl-hydrazine (USP 4,338,317)) was dissolved in a solution of potassium hydroxide (6.6 g) in ethyl alcohol (40 ml). The solvent was removed by evaporation under reduced pressure.
[0038] To the thus obtained residue ethyl N-(2-phenoxyethyl)carbamate, prepared as described in US-A-3,320,302, (20.9 g; 0.1 moles) and xylene (50 ml) were added at 50°C. The reaction mixture was quickly heated under vigorous stirring to 135-140°C and maintained at this temperature for 4 hours while removing the distillate.
[0039] Water (100 ml) was added and then 37% hydrochloric acid up to pH 4. A heavy oil was formed which was recovered and taken up in isoamyl alcohol (100 ml).
Example 2
2[3[4-(3-chlorophenyl)-1-piperazinyl]propyl]-4,5-diethyl-1,2,4-triazol-3-one (ethoperidone) hydrochloride (Formula I: R = R' = ethyl; R" = 3[4-(3-chlorophenyl)-1-piperazinyl]propyl).
[0041] The desired product was prepared following the same method as described in Example 1, except that the ethyl N-(2-phenoxyethyl)-carbamate (20.9 g; 0.1 moles) was substituted for N-ethyl-carbamate (17.6 g; 0.1 moles).
Example 3
5-ethyl-4-(2-phenoxyethyl)-1,2,4-triazol-3-one (Formula I: R' = PhOC2H4, R = C2H5, R" = H)
[0043] Propionyl hydrazine (53 g; 0.6 moles) was dissolved in a solution of potassium hydroxide (40 g) in ethyl alcohol (120 ml). The solvent was removed by evaporation under reduced pressure.
[0044] To the thus obtained residue ethyl N-(2-phenoxyethyl)carbamate (105 g; 0.5 moles) and xylene (250 ml) were added at 50°C. The reaction mixture was quickly heated under vigorous stirring to 135°C and maintained at this temperature for 4 hours while removing the distillate.
[0045] Xylene was completely removed by evaporation under reduced pressure. The residue obtained was taken up with water (250 ml) and the mixture heated to 80°C and made acid with 37% hydrochloric acid up to pH 4. A solid was formed, which was recovered by filtration at 20°C, washed and then dried. 95.5 g of the desired product was thus obtained which, after recrystallization, melts at 136°C.
Example 4
[0046] Working in a manner similar to that described in the previous examples the following products were prepared: 4,5-diphenyl-1,2,4-triazol-3-one; m.p. 160°C 4-phenyl-5-benzyl-1,2,4-triazol-3-one; m.p. 261-262°C 4-phenyl-5-isopropyl-1,2,4-triazol-3-one; m.p. 168°C 4-(4-chlorophenyl)-5-methyl-1,2,4-triazol-3-one; m.p. 172-174°C 4,5-diethyl-1,2,4-triazolone; m.p. 127-129°C 4-(2-chlorophenyl)-5-phenyl-1,2,4-triazol-3-one; m.p. 209°C.
1. A process for preparing a 1,2,4-triazol-3-one compound of the formula:
where
an ester of an N-substituted carbamic acid of the formula:
R'-NH-COOY (X)
where
R"-NH-NH-CO-R (XI)
where
R and R" have the above mentioned meanings,
in the presence of a strong base.
where
R is phenyl or C1-C10 alkyl optionally substituted by a phenyl group,
R' is phenyl, halophenyl or C1-C10 alkyl optionally substituted by phenyl or phenoxy,
R" is hydrogen or C1-C10 alkyl optionally substituted by a heterocyclic group,
characterized in thatan ester of an N-substituted carbamic acid of the formula:
R'-NH-COOY (X)
where
R' has the above mentioned meaning, and
Y is C1-C5 alkyl,
is reacted with a hydrazide of an aliphatic or aromatic carboxylic acid of the formula:R"-NH-NH-CO-R (XI)
where
R and R" have the above mentioned meanings,
in the presence of a strong base.
2. A process according to claim 1, characterized in that the strong base is an alkali
metal hydroxide, an alkali metal alcoholate, sodium hydride or sodium amide.
3. A Process according to claim 2, characterized in that the alkali metal is sodium or
potassium.
4. A process according to claim 1, characterized in that the reaction is carried out
in the presence of a diluent at a temperature of from -40°C to 200°C.
5. A process according to the preceding claims 3 and 4, characterized in that the strong
base is sodium hydride, a sodium or potassium hydroxide or alcoholate or a mixture
thereof and the diluent is immiscible or very poorly miscible with water at the boiling
temperature.
6. A process according to claim 5, characterized in that the diluent is methylcyclohexane,
toluene or xylene.
7. A process according to the preceding claims 2 or 4, characterized in that the strong
base is sodium amide and the diluent is liquid ammonia.
8. A process according to any one of the preceding claims from 1 to 7, characterized
in that R' is phenyl, chlorophenyl, methyl, ethyl or phenoxyethyl.
9. A process according to any one of the preceding claims from 1 to 8, characterized
in that R" is hydrogen or 4-(halophenyl)-1-piperazinyl-propyl.
10. A process according to any one of the preceding claims from 1 to 9, characterized
in that R is phenyl, methyl, ethyl, propyl, isooropyl, hexyl or benzyl.
1. Verfahren zur Herstellung einer 1,2,4-Triazol-3-on-Verbindung der Formel
worin R Phenyl oder C1-10-Alkyl, wahlweise substituiert durch eine Phenylgruppe, R' Phenyl, Halophenyl oder C1-10-Alkyl, wahlweise substituiert durch Phenyl oder Phenoxy,
R" Wasserstoff oder C1-10-Alkyl, wahlweise substituiert durch eine heterozyklische Gruppe sind, dadurch gekennzeichnet, daß ein Ester einer N-substituierten Carbaminsäure der Formel
R'-NH-COOY (X)
worin R' die oben erwähnte Bedeutung hat und Y C1-5-Alkyl ist, mit einem Hydrazid einer aliphatischen oder aromatischen Carbonsäure der Formel:
R"-NH-NH-CO-R (XI)
worin R und R" die oben angegebenn Bedeutungen haben, in der Gegenwart einer starken Base reagiert wird.
worin R Phenyl oder C1-10-Alkyl, wahlweise substituiert durch eine Phenylgruppe, R' Phenyl, Halophenyl oder C1-10-Alkyl, wahlweise substituiert durch Phenyl oder Phenoxy,
R" Wasserstoff oder C1-10-Alkyl, wahlweise substituiert durch eine heterozyklische Gruppe sind, dadurch gekennzeichnet, daß ein Ester einer N-substituierten Carbaminsäure der Formel
R'-NH-COOY (X)
worin R' die oben erwähnte Bedeutung hat und Y C1-5-Alkyl ist, mit einem Hydrazid einer aliphatischen oder aromatischen Carbonsäure der Formel:
R"-NH-NH-CO-R (XI)
worin R und R" die oben angegebenn Bedeutungen haben, in der Gegenwart einer starken Base reagiert wird.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß die starke Base ein Alkalimetallhydroxid,
ein Alkalimetallalkoholat, Natriumhydrid oder Natriumamid ist.
3. Verfahren nach Anspruch 2, dadurch gekennzeichnet, daß das Alkalimetall Natrium oder
Kalium ist.
4. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß die Reaktion in der Gegenwart
eines Verdünnungsmittels bei einer Temperatur von -40 bis 200°C durchgeführt wird.
5. Verfahren nach einem der vorhergehenden Ansprüche 3 und 4, dadurch gekennzeichnet,
daß die starke Base Natriumhydrid, ein Natrium- oder Kaliumhydroxid oder -alkoholat
oder eine Mischung davon und das Verdünnungsmittel mit Wasser bei der Siedetemperatur
unmischbar oder sehr gering mischbar ist.
6. Verfahren nach Anspruch 5, dadurch gekennzeichnet, daß das Verdünnungsmittel Methylcyclohexan,
Toluol oder Xylol ist.
7. Verfahren nach einem der vorhergehenden Ansprüche 2 oder 4, dadurch gekennzeichnet,
daß die starke Base Natriumamid und das Verdünnungsmittel flüssiges Ammoniak sind.
8. Verfahren nach einem der vorhergehenden Ansprüche 1 bis 7, dadurch gekennzeichnet,
daß R' Phenyl, Chlorphenyl, Methyl, Ethyl oder Phenoxyethyl ist.
9. Verfahren nach einem der vorhergehenden Ansprüche 1 bis 8, dadurch gekennzeichnet,
daß R" Wasserstoff oder 4-(Halophenyl)-1-piperazinylpropyl ist.
10. Verfahren nach einem der vorhergehenden Ansprüche 1 bis 9, dadurch gekennzeichnet,
daß R Phenyl, Methyl, Ethyl, Propyl, Isopropyl, Hexyl oder Benzyl ist.
1. Procédé de préparation d'un composé 1,2,4-triazol-3-one de formule :
où
on fait réagir un ester d'un acide carbamique N-substitué de formule :
R'-NH-COOY (X)
où
R"-NH-NH-CO-R (XI)
R et R" ont les significations données ci-dessus,
en présence d'une base forte.
où
R est un phényle ou alkyle C1-C10 éventuellement substitué par un groupe phényle,
R' est un phényle, halophényle ou alkyle C1-C10 éventuellement substitué par un phényle ou phénoxy,
R" est un hydrogène ou alkyle C1-C10 éventuellement substitué par un groupe hétérocyclique,
caractérisé en ce queon fait réagir un ester d'un acide carbamique N-substitué de formule :
R'-NH-COOY (X)
où
R' a la signification donnée ci-dessus, et
Y est un alkyle C1-C5,
avec un hydrazide d'un acide carboxylique aliphatique ou aromatique de formule :R"-NH-NH-CO-R (XI)
R et R" ont les significations données ci-dessus,
en présence d'une base forte.
2. Procédé selon la revendication 1, caractérisé en ce que la base forte est un hydroxyde
de métal alcalin, un alcoolate de métal alcalin, un hydrure de sodium ou un amide
de sodium.
3. Procédé selon la revendication 2, caractérisé en ce que le métal alcalin est le sodium
ou le potassium.
4. Procédé selon la revendication 1, caractérisé en ce qu'on réalise la réaction en présence
d'un diluant à une température de -40°C à 200°C.
5. Procédé selon les revendications précédentes 3 et 4, caractérisé en ce que la base
forte est un hydrure de sodium, l'hydroxyde de sodium ou de potassium ou un alcoolate
de sodium ou de potassium ou un de leurs mélanges et le diluant est non miscible ou
très peu miscible à l'eau à la température d'ébullition.
6. Procédé selon la revendication 5, caractérisé en ce que le diluant est le méthylcyclohexane,
le toluène ou le xylène.
7. Procédé selon les revendications précédentes 2 ou 4, caractérisé en ce que la base
forte est un amide de sodium et le diluant est l'ammoniac liquide.
8. Procédé selon l'une quelconque des revendications précédentes 1 à 7, caractérisé en
ce que R' est un phényle, chlorophényle, méthyle, éthyle ou phénoxyéthyle.
9. Procédé selon l'une quelconque des revendications précédentes 1 à 8, caractérisé en
ce que R" est l'hydrogène ou un 4-(halophényl)-1-pipérazinylpropyle.
10. Procédé selon l'une quelconque des revendications précédentes 1 à 9, caractérisé en
ce que R est un phényle, méthyle, éthyle, propyle, isopropyle, hexyle ou benzyle.